Reaction under Ball-Milling: Solvent- and Metal-Free One-Pot Diastereoselective Synthesis of Tetrahydroquinoline Derivatives as Potential Antibacterial and Anticancer Agents

Keya Roy; Anay Saha; Suprakash Sahoo; Subhrajyoti Banerjee; Chitrangada Das Mukhopadhyay; Subhash Banerjee; Laksmikanta Adak

doi:10.1055/a-2378-1847

Synlett, Table of Contents

Synlett 2024; 35(20): 2487-2495
DOI: 10.1055/a-2378-1847

letter

Special Issue to Celebrate the 75th Birthday of Prof. B. C. Ranu

Reaction under Ball-Milling: Solvent- and Metal-Free One-Pot Diastereoselective Synthesis of Tetrahydroquinoline Derivatives as Potential Antibacterial and Anticancer Agents

Keya Roy

^aDepartment of Chemistry, Indian Institute of Engineering Science and Technology, Shibpur, Botanic Garden, Howrah 711103, India

,

Anay Saha

^aDepartment of Chemistry, Indian Institute of Engineering Science and Technology, Shibpur, Botanic Garden, Howrah 711103, India

,

Suprakash Sahoo

^aDepartment of Chemistry, Indian Institute of Engineering Science and Technology, Shibpur, Botanic Garden, Howrah 711103, India

,

Subhrajyoti Banerjee

^bCenter of Healthcare Science and Technology, Indian Institute of Engineering Science and Technology, Shibpur, Botanic Garden, Howrah 711103, India

,

Chitrangada Das Mukhopadhyay

^bCenter of Healthcare Science and Technology, Indian Institute of Engineering Science and Technology, Shibpur, Botanic Garden, Howrah 711103, India

,

Subhash Banerjee

^cDepartment of Chemistry, Guru Ghasidas Vishwavidyalaya, Koni, Bilaspur, PIN 495009, Chhattisgarh, India

,

Laksmikanta Adak∗

^aDepartment of Chemistry, Indian Institute of Engineering Science and Technology, Shibpur, Botanic Garden, Howrah 711103, India

› Author Affiliations

Abstract

All articles of this category

This paper is dedicated to Professor Brindaban C. Ranu on the occasion of his 75^th birthday.

Abstract

A mild and efficient one-pot, three-component ball-mill-assisted reaction of aldehydes, anilines, and dihydrofuran (or dihydropyran and cyclohexenone) has been described for the first time in the presence of the catalytic amount of aqueous perchloric acid (8 mol%) at room temperature under organic solvent- and metal-free conditions. The reactions are fast (1 h), providing the products with excellent yields and high diastereoselectivity. This procedure endows a simple, efficient, and cost-effective method for the diastereoselective synthesis of furano- and pyrano-tetrahydroquinolines and phenanthridinone derivatives, which are important biological compounds. The diastereomers with cis configuration were isolated as major products. The H–H COSY, NOESY experiments and X-ray crystallographic analysis of selected compounds were performed to confirm the cis isomer. The synthesized tetrahydroquinolines have been evaluated in vitro for their antibacterial and anticancer activities, and it was found that both the prepared compounds showed significant antibacterial and anticancer properties.

Key words

ball-milling - solvent-free - diastereoselective synthesis - tetrahydroquinoline derivatives - antibacterial agent - anticancer agent

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References

References and Notes

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32 Representative Experimental Procedure for the Synthesis of (3aS,4S,9bS)-4-Phenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (4a, cisIsomer) A mixture of aniline (186 mg, 2 mmol), benzaldehyde (212 mg, 2 mmol), 2,3-dihydrofuran (210 mg, 3 mmol), and aqueous perchloric acid (70%, 16.1 mg, 8 mol%) adsorbed on neutral alumina (6 g) was ball-milled in a 50 mL stainless-steel beaker with five balls (d = 10 mm) of the same material at 350 rpm for 1 h. The ball-milling operation was performed using inverted rotation directions, with an interval of 15 min and taking an interval break of 30 s. Extraction of the reaction residue by simple elution with ethyl acetate followed by evaporation of the solvent gave the crude product, which was purified by column chromatography over silica gel (60–120 mesh) using a 5% ethyl acetate/hexane mixed solvent as eluant to give cis 4-phenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline as a white solid (462 mg, 92% yield, diastereoselective ratio cis:trans = 92:8). The identity and purity of products were confirmed by ¹H NMR and ¹³C NMR spectroscopic analysis and HRMS analysis. 3aS,4S,9bS)-4-Phenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (4a, cisIsomer) White solid; mp 93–95 ℃. IR (neat): ν = 3327, 2976, 2873, 1605, 1480, 1259, 1054, 1025 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.49–1.59 (m, 1 H), 2.16–2.29 (m, 1 H), 2.75–2.85 (m, 1 H), 3.73 (q, J = 11.1 Hz, 1 H), 3.84 (td, J = 11.2, 4.4 Hz, 2 H), 4.70 (d, J = 3.7 Hz, 1 H), 5.29 (d, J = 8.9 Hz, 1 H), 6.61 (d, J = 10.7 Hz, 1 H), 6.83 (t, J = 9.9 Hz, 1 H), 7.11 (t, J = 10.1 Hz, 1 H), 7.30–7.49 (m, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 24.8, 45.9, 57.6, 66.9, 76.1, 115.0, 119.3, 122.8, 126.6 (2 C), 127.8, 128.5, 128.8 (2 C), 130.2, 142.3, 145.1. HRMS (EI⁺): m/z [M]⁺ calcd for C₁₇H₁₇NO: 251.1310; found: 251.1313. (3aS,4S,9bS)-6-Fluoro-4-phenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (4b, cisIsomer) White solid; mp 106–108 °C. IR (neat): ν = 3376, 2911, 2843, 1618, 1484, 1208, 1044 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.51–1.58 (m, 1 H), 2.14–2.25 (m, 1 H), 2.76–2.83 (m, 1 H), 3.70–3.76 (m, 1 H), 3.82 (td, J = 8.8, 3.2 Hz, 1 H), 4.14 (s, 1 H), 4.71 (d, J = 2.8 Hz, 1 H), 5.28 (d, J = 7.8 Hz, 1 H), 6.69–6.74 (m, 1 H), 6.88–6.93 (m, 1 H), 7.14 (d, J = 7.7 Hz, 1 H), 7.30–7.41 (m, 3 H), 7.44–7.49 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 24.6, 45.7, 57.0, 67.0, 75.6, 113.6 (d, J = 18 Hz, 1 C), 118.1 (d, J = 7.0 Hz, 1 C), 125.0 (d, J = 2.0 Hz, 1 C), 125.1 (d, J = 3.0 Hz, 1 C), 126.6 (2 C), 127.9, 128.9 (2 C), 133.6 (d, J = 12.0 Hz, 1 C), 141.8, 151.0 (d, J = 238.0 Hz, 1 C). HRMS (EI⁺): m/z [M]⁺ calcd for C₁₇H₁₆FNO: 269.1216; found: 269.1216. (3aS,4S,9bS)-4-(p-Tolyl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (4g,cisIsomer) Orangish yellow solid; mp 106–108 °C. IR (neat): ν = 3314, 2910, 2874, 1598, 1481, 1290, 1048 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.50–1.58 (m, 1 H), 2.16–2.26 (m, 1 H), 2.37 (s, 3 H), 2.75–2.78 (m, 1 H), 3.70–3.83 (m, 3 H), 4.67 (d, J = 2.8 Hz, 1 H), 5.27 (d, J = 7.9 Hz, 1 H), 6.61 (d, J = 7.9 Hz, 1 H), 6.81 (td, J = 7.2, 0.8 Hz, 1 H), 7.09 (t, J = 7.8 Hz, 1 H), 7.20 (d, 7.9 Hz, 2 H), 7.31–7.41 (m, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 21.2, 24.8, 45.9, 57.4, 67.0, 76.1, 115.0, 119.2, 122.8, 126.5 (2 C), 128.5, 129.4 (2 C), 130.2, 137.5, 139.3, 145.2. HRMS (EI⁺): m/z [M]⁺ calcd for C₁₈H₁₉NO: 265.1467; found: 265.1465. (4aS,5S,10bS)-5-Phenyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline (4h, cis Isomer) White solid; mp 128–130 °C. IR (neat): ν = 3313, 2939, 2865, 1605, 1487, 1274, 1062 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.30–1.34 (m, 1 H), 1.41–1.46 (m, 1 H), 1.51–1.59 (m, 2 H), 2.15–2.21 (m, 1 H), 3.45 (td, J = 9.1, 2.6 Hz, 1 H), 3.58–3.62 (m, 1 H), 3.88 (br s, 1 H), 4.70 (d, J = 2.4 Hz, 1 H), 5.34 (d, J = 5.6 Hz, 1 H), 6.61 (dd, J = 7.9, 0.6 Hz, 1 H), 6.78–6.81 (td, J = 7.7, 0.7 Hz, 1 H), 7.11 (td, J = 7.9, 0.6 Hz, 1 H), 7.30–7.34 (m, 1 H), 7.37–7.45 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃): δ = 18.2, 25.6, 39.1, 59.5, 60.8, 72.9, 114.5, 118.4, 120.0, 126.9 (2 C), 127.6, 127.8, 128.2, 128.5 (2 C), 141.3, 145.3. HRMS (EI⁺): m/z [M]⁺ calcd for C₁₈H₁₉NO: 265.1467; found: 265.1467. (4aS,5S,10bS)-5-(Naphthalen-1-yl)-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline (4l, cis Isomer) Yellow solid; mp 130–132 °C. IR (neat): ν = 3380, 2903, 2837, 1598, 1481, 1304, 1268,1055 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.17–1.20 (m, 1 H), 1.39–1.66 (m, 3 H), 2.45–2.51 (m, 1 H), 3.46 (td, J = 10.6, 2.8 Hz, 1 H), 3.60 (dd, J = 11.3, 4.3 Hz, 1 H), 3.89 (br s, 1 H), 5.50–5.52 (m, 2 H), 6.69 (d, J = 7.8 Hz, 1 H), 6.85 (t, J = 7.52 Hz, 1 H), 7.15 (t, J = 7.4 Hz, 1 H), 7.50–7.59 (m, 4 H), 7.82 (t, J = 7.7 Hz, 2 H), 7.91–7.94 (m, 1 H), 7.98 (d, J = 8.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 18.7, 25.5, 36.7, 55.1, 60.8, 72.8, 114.8, 118.5, 120.3, 122.4, 123.8, 125.2, 125.8, 126.5, 127.9, 128.1, 128.2, 129.3, 130.5, 134.0, 136.2, 145.7. HRMS (EI⁺): m/z [M]⁺ calcd for C₂₂H₂₁NO: 315.1623; found: 315.1623. (3aS,4S,9bS)-4-(Thiophen-2-yl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (4o, cis Isomer) Brown solid; mp 90–92 °C. IR (neat): ν = 3357, 2910, 2874, 1598, 1466, 1253, 1048 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.91–1.99 (m, 1 H), 2.40–2.50 (m, 1 H), 2.97–3.05 (m, 1 H), 3.65 (q, J = 7.2 Hz, 1 H), 3.91–4.00 (m, 2 H), 5.15 (d, J = 2.9 Hz, 1 H), 5.43 (d, J = 7.8 Hz, 1 H), 6.76 (d, J = 8 Hz, 1 H), 7.00 (td, J = 7.2, 0.4 Hz, 1 H), 7.17–7.19 (m, 1 H), 7.24–7.28 (m, 2 H), 7.42–743 (m, 1 H), 7.52 (d, J = 7.5 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 25.3, 46.1, 53.8, 66.7, 75.8, 115.1, 119.7, 122.9, 124.2, 124.4, 126.8, 128.5, 130.2, 144.5, 145.6. HRMS (EI⁺): m/z [M]⁺ calcd for C₁₅H₁₅NOS: 257.0874; found: 257.0870.> (3aS,4R,9bS)-4-Heptyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (7a, cis Isomer) Yellow solid; mp 58–60 °C. IR (neat): ν = 3335, 2918, 2844, 1598, 1481, 1290, 1055 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.89–0.93 (m, 5 H), 1.31–1.35 (m, 9 H), 1.50–1.54 (m, 2 H), 1.81–1.89 (m, 1 H), 1.98–2.08 (m, 1 H), 2.58–2.66 (m, 1 H), 3.40–3.44 (m, 1 H), 3.78–3.82 (m, 2 H), 5.12 (d, J = 7.9 Hz, 1 H), 6.51 (d, J = 7.8 Hz, 1 H), 6.75 (t, J = 6.8 Hz, 1 H), 7.04 (td, J = 7.4, 1.2 Hz, 1 H), 7.30 (d, J = 7.5 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.2, 22.8, 24.1, 26.0, 29.3, 29.8, 31.9, 34.5, 42.6, 52.6, 66.7, 75.9, 114.5, 118.7, 123.0, 128.3, 130.2, 145.2. HRMS (EI⁺): m/z [M]⁺ calcd for C₁₈H₂₇NO: 273.2093; found: 273.2096. (3aS,4S,9bS)-4-(tert-Butyl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (7d, cis Isomer) Pale green solid; mp 104–106 °C. IR (neat): ν = 3350, 2947, 2881, 1598, 1473, 1298, 1055 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.05 (s, 9 H), 1.83–1.91 (m, 1 H), 2.03–2.13 (m, 1 H), 2.68–2.75 (m, 1 H), 3.22 (d, J = 1.8 Hz, 1 H), 3.50–3.88 (m, 3 H), 5.18 (d, J = 7.5 Hz, 1 H), 6.55 (d, J = 8.0 Hz, 1 H), 6.75 (d, J = 7.6 Hz, 1 H), 7.04 (td, J = 7.6 Hz, 1 H), 7.31 (d, J = 7.56 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 24.6, 27.4(3C), 33.7, 39.9, 61.4, 67.1, 77.6, 114.6, 118.5, 122.6, 128.2, 129.8, 145.6. HRMS (EI⁺): m/z [M]⁺ calcd for C₁₅H₂₁NO: 231.1623; found: 231.1623. (6S,6aR,10aS)-2-Methyl-6-phenyl-5,6a,7,8,9,10a-hexahydrophenanthridin-10(6H)-one (10c, cis Isomer) Yellow liquid. IR (neat): ν = 3365, 2918, 2844, 1715, 1605, 1510, 1209 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.64–1.72 (m, 1 H), 1.94–2.15 (m, 2 H), 2.19 (s, 3 H), 2.22–2.27 (m, 2 H), 2.42 (dd, J = 18.8, 2.5 Hz, 1 H), 2.69–2.75 (m, 2 H), 4.47 (s, 1 H), 4.58 (d, J = 2.4 Hz, 1 H), 6.54 (d, J = 8.6 Hz, 2 H), 6.95 (d, J = 8.4 Hz, 2 H), 7.17–7.22 (m, 1 H), 7.27–7.34 (m, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 20.3, 22.6, 22.7, 46.0, 48.8, 52.3, 66.0, 113.4 (2 C), 125.7 (2 C), 127.0, 127.5, 129.0 (2 C), 129.9 (2 C), 142.0, 146.0, 212.1. HRMS (FAB⁺): m/z [M + H]⁺ calcd for C₂₀H₂₂NO: 292.1701; found: 292.1701.

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